Sex‐Specific Proteomic Profiling Identifies Pregnancy Zone Protein as a Complement‐Linked Marker of Adverse Prognosis in Esophageal Adenocarcinoma

ABSTRACT

Esophageal adenocarcinoma (EAC) exhibits marked male predominance with male‐to‐female ratios reaching 8.5:1, yet the molecular basis underlying this sex disparity remains poorly characterized. We analyzed 92 EAC specimens using mass spectrometry–based proteomics, comprising 47 female and 45 male tumors from treatment‐naïve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex‐associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in EAC. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y‐chromosome–encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune‐related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival specifically in male patients, with no significant association detected in the combined or female‐only cohort. Proteome‐wide survival analyses further demonstrated distinct sex‐specific prognostic landscapes. Our study provides the first comprehensive characterization of sex‐associated proteomic differences in EAC. Sex shapes immune‐related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex‐differential, complement‐associated protein with adverse prognostic significance in male patients, highlighting sex as a biologically and clinically relevant variable in EAC.